Synthetic pesticides have adverse effects on both the environment and human health. These chemical compounds can leave residues that contaminate food, water, and soil, thereby posing risks to consumers, workers, and bystanders exposed to pesticides. The primary objective of this study was to determine the levels of pesticide residues in water, fish, and sediment samples collected from various locations in Lake Manzala, Egypt. Additionally, the study aimed to assess the health risks associated with consuming tilapia fish from Lake Manzala, which is known to be contaminated with pesticide residues. Water, sediment, and fish samples were collected from five different locations within Lake Manzala. The samples were analyzed for the presence of pesticide residues, 402 pesticides. For each detected pesticide, the study calculated the Estimated Daily Intake (EDI) and the Hazard Index (HI), considering both individual and combined residues. Results showed that a total of 22 pesticides were detected in water samples, 24 in sediment samples, and 20 in fish samples. The type and concentration of pesticides varied across the sampling locations. Notably, Genka El-Mataria, Bahr El Baqur, and the Old Sea Outlet had the highest pesticide residues. The most common pesticides found in all samples included Cadusafos, Cyprodinil, Thiram, aldicarb-sulfone-NH4+, and cyfluthrin-NH4+. The environmental samples (water, sediment, and fish) contained a total of 42 pesticide residues, spanning different categories: 18 insecticides, 13 herbicides, 9 fungicides, 1 nematicide, and 1 parasitic pesticide. Of the detected residues, 60.71% were from registered pesticides, while 39.29% were from unregistered or discontinued ones. The most prevalent chemical groups were pyrethroids, dinitroaniline, and organophosphorus compounds. The findings of our study indicate that the pesticide concentrations in the fish samples from Lake Manzala were below the acceptable daily intake (ADI) threshold. Furthermore, the health risk index (HI) for each individual pesticide, as well as their combined effect, was lowers than 1 (HI < 1). Consequently, the fish from Lake Manzala are deemed safe for consumption and do not pose any human health hazards related to pesticide exposure.